rs7190823

Positions:

chr16-89799635-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.796A>G(p.Thr266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,607,974 control chromosomes in the GnomAD database, including 184,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23670 hom., cov: 33)

Exomes 𝑓: 0.45 ( 160530 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.671

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1698945E-6).

BP6

Variant 16-89799635-T-C is Benign according to our data. Variant chr16-89799635-T-C is described in ClinVar as [Benign]. Clinvar id is 134294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89799635-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.796A>G	p.Thr266Ala	missense_variant	9/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.796A>G	p.Thr266Ala	missense_variant	9/43		NP_001273096.1	O15360-3
FANCA	NM_001018112.3 link	c.796A>G	p.Thr266Ala	missense_variant	9/11		NP_001018122.1	O15360-2
FANCA	NM_001351830.2 link	c.700A>G	p.Thr234Ala	missense_variant	8/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.796A>G	p.Thr266Ala	missense_variant	9/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.531

AC:

80719

AN:

152034

Hom.:

23636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.717

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.981

Gnomad SAS

AF:

0.628

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.465

GnomAD3 exomes

AF:

0.521

AC:

130900

AN:

251338

Hom.:

38559

AF XY:

0.509

AC XY:

69125

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.668

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.984

Gnomad SAS exome

AF:

0.590

Gnomad FIN exome

AF:

0.469

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.453

AC:

658793

AN:

1455822

Hom.:

160530

Cov.:

AF XY:

0.454

AC XY:

328778

AN XY:

724642

show subpopulations

Gnomad4 AFR exome

AF:

0.723

Gnomad4 AMR exome

AF:

0.653

Gnomad4 ASJ exome

AF:

0.323

Gnomad4 EAS exome

AF:

0.980

Gnomad4 SAS exome

AF:

0.589

Gnomad4 FIN exome

AF:

0.461

Gnomad4 NFE exome

AF:

0.409

Gnomad4 OTH exome

AF:

0.468

GnomAD4 genome

AF:

0.531

AC:

80814

AN:

152152

Hom.:

23670

Cov.:

AF XY:

0.540

AC XY:

40187

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.717

Gnomad4 AMR

AF:

0.545

Gnomad4 ASJ

AF:

0.327

Gnomad4 EAS

AF:

0.981

Gnomad4 SAS

AF:

0.628

Gnomad4 FIN

AF:

0.474

Gnomad4 NFE

AF:

0.399

Gnomad4 OTH

AF:

0.471

Alfa

AF:

0.428

Hom.:

39534

Bravo

AF:

0.547

TwinsUK

AF:

0.436

AC:

1616

ALSPAC

AF:

0.409

AC:

1576

ESP6500AA

AF:

0.726

AC:

3190

ESP6500EA

AF:

0.394

AC:

3386

ExAC

AF:

0.516

AC:

62710

Asia WGS

AF:

0.788

AC:

2740

AN:

3478

EpiCase

AF:

0.384

EpiControl

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	This variant is associated with the following publications: (PMID: 23021409, 24728327, 27153395) -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.2

DANN

Benign

0.16

DEOGEN2

Benign

0.072

T;.;.;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.023

T;T;T;T;T;T

MetaRNN

Benign

0.0000012

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

N;N;N;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

1.7

N;N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;.;B;.;B;B

Vest4

0.086

ClinPred

0.0032

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.078

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over